Drug delivery devices for setting and dispensing a single or multiple doses of a liquid medicament are as such well-known in the art. Generally, such devices have substantially a similar purpose as that of an ordinary syringe.
Drug delivery devices, in particular pen-type injectors have to meet a number of user-specific requirements. For instance, with patient's suffering chronic diseases, such like diabetes, the patient may be physically infirm and may also have impaired vision. Suitable drug delivery devices especially intended for home medication therefore need to be robust in construction and should be easy to use. Furthermore, manipulation and general handling of the device and its components should be intelligible and easy understandable. Moreover, a dose setting as well as a dose dispensing procedure must be easy to operate and has to be unambiguous.
Typically, such devices comprise a housing, adapted to receive a cartridge at least partially filled with the medicament to be dispensed. The device further comprises a drive mechanism, typically having a displaceable piston rod which is adapted to operably engage with a piston of the cartridge. By means of the drive mechanism and its piston rod, the piston of the cartridge is displaceable in a distal or dispensing direction and may therefore expel a predefined amount of the medicament via a piercing assembly, which is to be releasably coupled with a distal end section of the housing of the drug delivery device.
The medicament to be dispensed by the drug delivery device is provided and contained in a multi-dose cartridge. Such cartridges typically comprise a vitreous barrel sealed in distal direction by means of a pierceable seal and being further sealed in proximal direction by the piston. With reusable drug delivery devices an empty cartridge can be replaced by a new one. In contrast to that, drug delivery devices of disposable type are to be entirely discarded when the medicament in the cartridge has been dispensed or used-up.
With such multi-dose drug delivery devices at least a last dose limiting mechanism is required to inhibit setting of a dose exceeding the amount of medicament which is left in the cartridge. This is to avoid a potentially dangerous situation for the user believing that a set dose is entirely injected.
There already exist some drug delivery devices with such end-of-content mechanisms or last dose mechanisms.
Document WO 2009/132778 A1 for instance discloses a dose limiting member designed for axial movement in a proximal direction with respect to the piston rod during dose setting. The dose limiting member comprises a first stop element and the piston rod comprises a second stop element. First and second stop elements stop an axial movement of the dose limiting member in the proximal direction with respect to the piston rod when the first and second stop elements catch, thereby limiting a movement of the dose setting member for increasing a set dose of medication to be delivered. There, the dose limiting member and the piston rod only interact directly, when the first and second stop elements catch.
End-of-content mechanisms or last dose limiting mechanisms of drug delivery devices of e.g. pen-injector type are typically located and implemented to directly or indirectly engage with the piston rod of the drive mechanism. Since the axial position of the piston rod is unequivocally related to the axial position of the piston in the cartridge it provides a direct indication of the amount of medicament remaining in the cartridge.
Additionally or alternatively, last dose limiting mechanisms may also be implemented by the mechanical interaction of a drive sleeve being either directly or indirectly coupled and engaged with the piston rod, at least during a dose dispensing procedure.
With most of these known approaches the last dose limiting mechanism is located rather remote from an actuation member, such like a dose dial member, by way of which the user may interact with the drive mechanism, e.g. for setting and/or dispensing of a dose. For limiting or delimiting a dose setting procedure, the angular momentum or driving force exerted by a user of the device has to be transferred from the actuation member almost through the entire drive mechanism and the plurality of its mutually interacting components until the last dose limiting mechanism is eventually activated and blocks a further dose incrementing movement of the drive mechanism and of its various components.
Since the mechanically interacting components of a drive mechanism are always subject to inevitable mechanical tolerances, a respective tolerance chain extending between the actuation member and the last dose limiting mechanism is fairly long. In effect, once a last dose limiting mechanism is activated and actually inhibits a dose incrementing displacement of e.g. a drive sleeve relative to a housing or relative to a piston rod, the locking or blocking of e.g. the drive sleeve has to propagate and to be transferred or returned to the actuation member. Also here, due to the tolerance chain at least a minimal displacement, e.g. rotation of the actuation member, may still be possible even though a dose incrementing displacement of the drive mechanism is effectively blocked.
It is therefore an object of the present invention to avoid disadvantages of known drug delivery devices and to provide an improved last dose limiting mechanism.
It is another object of the present invention to provide a drive mechanism for a drug delivery device for setting and dispensing of a dose of a medicament typically provided in a cartridge, wherein the drive mechanism is equipped with a last dose limiting mechanism. It is a further object to provide an alternative end-of-content mechanism or an alternative last dose limiting mechanism operable to provide an accurate and immediate feedback to the user of the device in a last dose limiting configuration. Moreover, the last dose limiting mechanism should be highly reliable and robust.
In a further aspect the invention aims to provide a drug delivery device comprising such a drive mechanism and comprising a cartridge sealed with a piston to become operably engaged with a piston rod of such drive mechanism.
The present invention provides a drive mechanism for a drug delivery device for dispensing of a dose of a medicament. The drive mechanism comprises an elongated housing extending in an axial direction. The elongated housing is typically of tubular or cylindrical shape and serves to accommodate mechanically interacting components of the drive mechanism that are required to displace a piston rod in a distal direction to engage with a piston of a cartridge being at least partially filled with a medicament to be dispensed by the drug delivery device.
The drive mechanism is typically operable to set and to dispense multiple doses of the medicament of variable size. Hence, the drive mechanism is operable in a dose setting mode for selecting or individually setting of a dose of the medicament. After setting of a dose, the set dose can be dispensed by the drive mechanism when switched into a dose dispensing mode. Operation of the drive mechanism in at least the dose setting mode can be controlled and driven by an actuation member rotatably supported on the housing for setting of the dose.
Optionally, the actuation member may also serve to operate the drive mechanism for dispensing of the previously set dose. Typically, the actuation member is located at a proximal end of the housing located opposite and facing away from a dispensing end of the drug delivery device.
The drive mechanism further comprises a last dose sleeve rotatably engageable with the actuation member at least during a dose setting procedure and having at least one stop to limit a displacement of a last dose member threadedly engaged with the last dose sleeve and being rotatably fixed to the housing. The last dose member also belongs to the drive mechanism and is adapted to lock, to block or to impede a dose incrementing displacement, i.e. a dose incrementing rotation of the last dose sleeve when a last dose limiting configuration of the drive mechanism has been reached. Preferably, the last dose sleeve is directly engaged with the actuation member. It may even be at least partially or entirely housed therein. Furthermore, the last dose sleeve may also be permanently rotatably engaged with the actuation member, even when the drive mechanism is in dose dispensing mode.
Preferably, the actuation member is rotatably supported on the housing and can be rotated in two opposite directions, in particular for incrementing and for decrementing a dose during a dose setting procedure. At least in the dose setting mode, the actuation member and the last dose sleeve are rotatably coupled and rotatably locked with respect to each other, so that a rotation of the actuation member relative to the housing is unalteredly transferred and coupled to or with a respective rotation of the last dose sleeve relative to the housing.
Since the last dose member is threadedly engaged with the last dose sleeve and since the last dose member is rotatably fixed to the housing, e.g. splined to the housing, the last dose member is forced to travel in axial direction relative to the housing and/or relative to the last dose sleeve during a dose setting procedure. Since the last dose member is rotatably fixed to the housing it cannot rotate neither with respect to the housing nor with respect to the last dose sleeve.
When the drive mechanism approaches or reaches a last dose limiting configuration, the last dose member abuts with or engages with the at least one stop, e.g. a last dose stop, thereby limiting and blocking a further dose incrementing rotation of the last dose sleeve. Since the last dose sleeve is directly engaged and mechanically coupled with the actuation member, the actuation member is correspondingly blocked and rotatably locked in the last dose limiting configuration. Moreover, since the actuation member is directly engaged with the last dose sleeve and since a rotation of the last dose sleeve relative to the housing can be blocked by a single last dose member which is directly engaged with the last dose sleeve and with the housing, a rather direct and robust feedback can be provided to a user of the device when the drive mechanism reaches the last dose limiting configuration.
By having the last dose sleeve in direct engagement with the actuation member, a tolerance chain of a last dose limiting mechanism is fairly short and the negative influence of inevitable mechanical tolerances and mechanical play between various functional and mutually engaging components of the drive mechanism can be reduced to a minimum.
Naturally, the travel path the last dose member is allowed to travel along the last dose sleeve is adapted and correlated to the maximum distance the piston rod of the drive mechanism may advance in distal direction during consecutive dose dispensing procedures. Accordingly, the threaded engagement of the last dose sleeve and the last dose member as well as the axial elongation of the last dose sleeve is designed and chosen accordingly in order to match with the size of the cartridge and the amount of medicament contained therein. Moreover, the axial position of the last dose member relative to the dose sleeve is unequivocally correlated and always corresponds to the axial position of the piston rod and hence to the axial position of the piston of the cartridge operably engaged with the piston rod of the drive mechanism.
According to a further embodiment, the last dose sleeve comprises an external thread mating with an internal thread of the last dose member. The internal thread of the last dose member at least partially surrounds the circumference of the threaded portion of the last dose sleeve. Hence, the last dose member, e.g. designed as a last dose nut, is arranged outside the last dose sleeve, on its outer circumference. Preferably, the last dose member surrounds the outer circumference of the last dose sleeve only partially in order to support an easy and intuitive assembly of last dose sleeve, last dose member and housing. By only partially surrounding the circumference of the last dose sleeve, the last dose member can be assembled on the last dose sleeve in radial direction between two axially separated stops of the last dose sleeve.
According to a further embodiment, the at least one stop extends radially outwardly at a distal and/or proximal end of the external thread of the last dose sleeve. Preferably, the external thread terminates at a distal as well as at a proximal end with one stop, respectively. The stop or stop element typically extends radially outwardly from a threaded portion of the last dose sleeve in order to provide a radial stop or radially extending stop face for the last dose member. Typically, the last dose member comprises a leading and a trailing edge in circumferential direction with respect to the sense of rotation of the last dose sleeve relative to the last dose member. By means of its leading and/or trailing edge, the last dose member may engage with the radially extending or radially protruding stop provided on the outer circumference of the last dose sleeve when reaching a last dose limiting configuration.
Generally, radially extending stops provide an accurate, well-defined and reproducable stop configuration for those components being equipped with such mutually engaging stop features. A radial stop generally provides a radially outwardly and/or radially inwardly extending structure provided at a particular tangential position on the inner and/or outer circumference of e.g. a tubular shaped component. In this way, a definite and well defined stop configuration can be provided which is much more precise and less sensitive to an eventual self-locking which may otherwise occur with an axial stop, such like a radially extending flange extending at a particular axial position of e.g. a last dose sleeve.
However, in alternative embodiments implementation of such axial stops is also generally conceivable, also in combination with radially acting stops.
When the leading or trailing edge of the last dose member abuts or engages with the at least one stop of the last dose sleeve, further rotation of the last dose sleeve can be effectively blocked and inhibited, thereby blocking or inhibiting a further dose incrementing rotation of the actuation member during a dose setting procedure. The radially and preferably also axially extending leading or trailing edge of the last dose member and the correspondingly shaped stop of the last dose sleeve are adapted to immediately block a further rotation of the last dose sleeve and hence of the actuation member when a predetermined rotational position of the last dose sleeve and the actuation member has been reached.
According to another embodiment, the last dose member comprises a radially outwardly extending protrusion engaged with an axially extending groove of the housing. In particular, the last dose member is radially sandwiched between the housing and the last dose sleeve. By means of the radially outwardly extending protrusion, the last dose member is splined to the housing and is hence rotatably fixed to the housing. In this context a splined engagement of at least two components means, that the two components are rotatably engaged but are free to move in an axial direction with respect to each other.
Mutually engaging protrusion and groove of the last dose member and the housing only support and allow for an axial displacement of the last dose member relative to the housing and relative to the last dose sleeve. Preferably, the radially outwardly extending protrusion of the last dose member is located midway between opposite circumferential ends, hence midway between trailing and leading edges of the last dose member. Such an arrangement of the protrusion is beneficial in terms of distribution of mechanical forces and momentum acting on the last dose member.
According to another embodiment the last dose member is arc-shaped and comprises a leading and a trailing edge in circumferential direction to engage with the at least one stop. In particular, the arc-shaped geometry of the last dose member corresponds with the outer circumference of the tubular-shaped threaded portion of the last dose sleeve. Preferably, the arc-shaped last dose member extends at most about 180° around the circumference of the last dose sleeve in order to allow for a radially directed mutual assembly of the last dose sleeve and the last dose member.
By having an arc-shaped last dose member extending at least about 90° along the outer circumference of the last dose sleeve, a rather robust, smooth running and reliable mechanical interaction between the last dose member and the last dose sleeve can be effectively provided.
According to a further embodiment, the last dose sleeve and the last dose member are located in a receptacle at a proximal end of the housing. The receptacle may be cup-shaped and allows for an axially and distally directed assembly of the last dose sleeve and the last dose member into the housing of the drive mechanism. Here, it is of particular benefit, when the arc-shaped last dose member is assembled in radial direction on the outer circumference of the last dose sleeve and when in a subsequent step of assembly the combined last dose member and last dose sleeve are corporately assembled and inserted in the proximal receptacle of the housing.
The receptacle of the housing is open in proximal direction to allow for a distally directed assembly of the dose sleeve and the last dose member into the receptacle. In proximal direction, the receptacle can be confined by a radially inwardly extending socket of the housing providing an axial stop and a radially inwardly extending stop face for the last dose sleeve. The receptacle may also receive a distally extending clutch to operably engage with the last dose sleeve and/or with the actuation member.
In a further embodiment, the actuation member is rotatably supported on the proximal end of the housing at least in a dose setting mode of the drive mechanism. The actuation member may be snapped on the proximal end of the housing and may therefore positively engage with the housing at least in axial direction. Hence, a distal end portion of the actuation member may comprise a radially inwardly extending snap feature or a correspondingly shaped flange portion to engage with a radially outwardly extending rim of the housing.
Moreover and according to a further embodiment the actuation member is cup-shaped and surrounds and closes the receptacle of the housing in proximal direction when assembled thereon. Here, the actuation member fulfils a double or even a triple function. First of all, the actuation member serves to transfer an angular momentum to the last dose sleeve and/or to further functional components of the drive mechanism operably engaged therewith. Second, the actuation member may control and trigger a dose dispensing procedure. Third, the actuation member actually seals and closes a proximal end of the housing of the drive mechanism and/or of the drug delivery device.
According to a further embodiment, the actuation member is axially displaceable relative to the housing from a proximal dose setting position to a distal dose dispensing position against the force of at least one spring element. By means of an at least small axial displacement of the actuation member, the drive mechanism is operable to switch between a dose setting mode and a dose dispensing mode. Preferably, axial displacement of the actuation member has no influence on the axial position of the last dose sleeve. Hence, the rotational engagement of the actuation member and the last dose sleeve allows for a mutual axial displacement of the actuation member relative to the last dose sleeve. Preferably, the actuation member is splined to the last dose sleeve for a transfer of angular momentum there between.
According to a further embodiment, the last dose sleeve comprises at least one axially extending recess to receive a correspondingly shaped distally extending journal of the actuation member. Preferably, the axial recess is located at a pre-determined distance from the radial center of the last dose sleeve to allow for a rotational engagement of the actuation member and the last dose sleeve by means of the journal extending into or reaching through the recess of the last dose sleeve. This type of mutual engagement allows for a rotational coupling of the last dose sleeve and the last dose member even at different axial positions of the actuation member relative to the last dose sleeve and/or relative to the housing. Hence, even in a dose dispensing mode, the last dose sleeve and the actuation member remain rotationally coupled and rotationally locked with respect to each other.
Preferably, the last dose sleeve comprises a circumferential rim at its proximal end extending in proximal direction and being interrupted by the at least one axial recess. The inside surface of the rim may flush and may extend into the inside facing portion or side wall of the tubular-shaped last dose sleeve. Hence, the axially extending recess or several recesses of the last dose sleeve are preferably arranged at or near a radially outwardly located circumference of the last dose sleeve in order to keep a mechanical load on the recesses at a minimum level during a rotating dose setting movement of the actuation member.
In a further preferred embodiment, the at least one spring element to engage with the actuation member is located on the last dose sleeve. The spring element is preferably helically shaped, extends in proximal direction from a proximal end of the last dose sleeve and abuts against the inside of a proximal end face of the actuation member. Preferably, there are provided at least two symmetrically arranged spring elements on diametrically opposite portions of the last dose sleeve. In particular, the at least one spring element is integrally formed with the last dose sleeve and may extend from the proximal and circumferentially extending rim located at the proximal end of the dose sleeve.
By means of the at least one spring element located on the last dose sleeve, the actuation member can be biased in proximal direction. Hence, distally directed displacement of the actuation member relative to the housing and/or relative to the last dose sleeve acts against the restoring force provided by the at least one spring element.
Moreover and according to another embodiment, the last dose sleeve comprises a radially extending flange portion at its distal end to axially abut with a radially inwardly extending socket portion of the housing. This way, the last dose sleeve is at least axially fixed in distal direction with regard to the housing. Since the actuation member preferably covers the proximal end of the housing and since the actuation member is axially fixed in proximal direction with respect to the housing, mutual assembly of the housing, of the last dose sleeve and the actuation member, e.g. distally clipped on the housing, comes along with a tensioning of the at least one spring element of the last dose sleeve.
In this way, the at least one spring element not only serves to displace the actuation member in proximal direction during switching of the drive mechanism from a dose dispensing mode into a dose setting mode. Moreover, by way of the at least one spring element the last dose sleeve is also axially secured relative to the housing with respect to the proximal direction.
The radially extending flange portion of the last dose sleeve may also act as a support for the at least one stop extending in radial direction from the external thread of the dose sleeve. Accordingly, the last dose sleeve may also comprise a radially extending flange portion at its proximal end in order to support a correspondingly shaped proximal stop to interact with the last dose member to block and to limit a rotation of the last dose sleeve and the actuation member operably coupled therewith.
Additionally, the two oppositely located radially extending flange portions of the dose sleeve may serve as a guiding structure to support a smooth rotation of the actuation member inside the housing. Hence, the radially outwardly located surface portions of the distal and the proximal flange portions of the last dose sleeve may serve as plain or slide bearings for the rotational movement of the last dose sleeve inside the receptacle of the housing. Hence, the radially outwardly facing side surfaces of the distal and proximal flange portions of the last dose sleeve may glide along an inside facing inner surface of the receptacle of the housing in circumferential direction.
According to another embodiment, the last dose sleeve is also rotatably supported on a sleeve-shaped clutch at least partially extending in axial direction into the interior of the last dose sleeve. Here, the clutch may provide a radially inwardly located bearing for the last dose sleeve. The inside facing sidewall of the last dose sleeve and a correspondingly shaped outside facing portion of the clutch are substantially even shaped and are therefore free of protrusions to allow for a smooth rotation of the last dose sleeve relative to the clutch. In particular, the last dose sleeve is radially sandwiched between the receptacle of the housing and the clutch.
According to a further embodiment, the last dose sleeve comprises a toothed surface at a distal end of its radially inwardly facing sidewall to selectively engage with correspondingly shaped and radially outwardly extending teeth of the clutch. It is of particular benefit, when the last dose sleeve is rotatably coupled and hence rotatably fixed to the clutch during a dose setting procedure and when the last dose sleeve, e.g. by way of a distally directed displacement of the clutch is rotatably releasable from the clutch during a dose dispensing procedure. The clutch in turn may be rotatably coupled with further functional components of the drive mechanism, such like a drive sleeve, which is either directly or indirectly engageable with the piston rod for initiating a distally directed longitudinal displacement of the piston rod during a dose dispensing procedure.
Preferably, a distally directed displacement of the clutch can be achieved by a corresponding distally directed displacement of the actuation member. Hence, the actuation member may abut with a proximal end, e.g. with a proximally located rim of the clutch by means of at least one distally extending journal. Starting from an initial configuration, in which the actuation member rests in a proximal position, which corresponds to the dose setting mode of the drug delivery device, a distally directed displacement of the actuation member is almost unalteredly and directly transferable to a corresponding distally directed displacement of the clutch, thereby disengaging the rotational coupling of the clutch and the last dose sleeve.
With the distally directed dose dispensing displacement of the actuation member, the actuation member may engage with radially inwardly extending teeth or radially inwardly extending protrusions with a toothed ring provided at the outer circumference of the housing, thereby rotatably interlocking the actuation member and the housing. Since the last dose sleeve is rotatably released and decoupled from the clutch and since the actuation member is rotatably fixed and engaged with the housing during a dose dispensing procedure, the clutch may rotate for advancing the piston rod in distal direction while the last dose sleeve remains rather stationary for not further modifying the axial position of the last dose member on the actuation member.
If for instance a dose dispensing procedure is interrupted by prematurely releasing the actuation member, the actuation member will return into its proximal position under the effect of the at least one spring element located on the proximal end of the last dose sleeve. Additionally, the clutch may be accordingly spring biased in axial direction relative to the housing. For this purpose, either the clutch or the housing comprises at least one spring element, which provides a restoring- and proximally directed spring force to axially displace the clutch in proximal direction at the end of a dose dispensing procedure.
Under the effect of this additional spring element, the clutch may automatically return into a rotational engagement configuration with the last dose sleeve. Moreover, since the actuation member may axially abut with the clutch, distally directed displacement of the clutch, e.g. for triggering and initiating a dose dispensing procedure, may occur against the action of two separate spring elements, one of which acting between the last dose member and the actuation member and the other of which acting and being located between the housing and the clutch. Naturally, the housing and the clutch comprise mutually corresponding radially inwardly and/or radially outwardly extending protrusions, between which a respective spring element may extend in axial direction.
In general, the last dose mechanism according to the present invention is functionally located between an actuation member, to be directly operated and manipulated by a user of the device, and force- or momentum transmitting components of the drive mechanism. In terms of a flow of force or flow of momentum provided by the drive mechanism, in particular during a dose setting procedure, the last dose limiting mechanism is located upstream of a clutch, upstream of a drive sleeve, upstream of a drive nut as well as upstream of a piston rod of the drive mechanism.
In particular the last dose limiting mechanism directly engages with the actuation member of the drive mechanism which is to be manually operated by a user of the device. In this way, a comparatively direct and robust as well as reliable feedback can be provided to a user of the device when the last dose limiting configuration of the drive mechanism has been reached.
According to another aspect, the invention also relates to a drug delivery device for dispensing of a dose of a medicament. The drug delivery device comprises a drive mechanism as described above and a cartridge at least partially filled with the medicament to be dispensed by the drug delivery. The cartridge is arranged in the housing of the drive mechanism or in a cartridge holder of the drug delivery device which is fixed to the housing either releasably or non-releasably, e.g. in case of a disposable drug delivery device. Consequently, the drug delivery device comprises a cartridge holder to receive and to accommodate a cartridge filled with the medicament.
The cartridge holder may be non-releasably engaged and connected to the proximal housing, e.g. by means of bonding or welding. For reusable drug delivery devices it is of particular benefit when the cartridge holder is detachable from the housing for providing access to the cartridge located therein, in particular for replacing the cartridge. A detachable connection of cartridge holder and housing can be attained by means of mutually corresponding threaded portions of cartridge holder and housing, respectively. Alternatively, it is also conceivable that cartridge holder and proximal housing of the drug delivery device are integrally formed.
Apart from that, the drug delivery device and the drive mechanism may comprise further functional components, such like an actuation member, by way of which a user may operate or manipulate the drug delivery device and its drive mechanism for setting and correcting as well as for dispensing of a correspondingly set dose.
Moreover, the drive mechanism and the drug delivery device may also comprise a dose indicating sleeve, which may rotate together with the drive sleeve and which may provide a visual indication to the user regarding the size of the dose actually set.
In the present context, the distal direction points in the direction of the dispensing and of the device, where, preferably a needle assembly is provided having a double-tipped injection needle that is to be inserted into biological tissue or into the skin of a patient for delivery of the medicament.
The proximal end or proximal direction denotes the end of the device or a component thereof, which is furthest away from the dispensing end. Typically, an actuating member is located at the proximal end of the drug delivery device, which is directly operable by a user to be rotated for setting of a dose and which is operable to be depressed in distal direction for dispensing of a dose.
The drive mechanism particularly serves to displace a piston rod in axial direction for the purpose of dispensing of a dose of a medicament. In addition, the drive mechanism typically comprises components which also form part of and have a function in at least one of the following mechanisms: a dose setting mechanism, a last dose limiting mechanism and a dose indicating mechanism. As will be apparent from the embodiments described herein various components of e.g. the drive mechanism also belong to at least one of the dose setting mechanism, the last dose limiting mechanism and/or to the dose indicating mechanism; and vice versa. Hence, the invention as described herein equally refers to and defines a drive mechanism, a dose setting mechanism, a last dose limiting mechanism and/or a dose indicating mechanism of a drug delivery device.
The term “drug” or “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound,
wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a proteine, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound,wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis,wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4.
Insulin analogues are for example Gly(A21), Arc(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.
Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.
Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.
Exendin-4 derivatives are for example selected from the following list of compounds:
H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
des Pro36 Exendin-4(1-39),
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),
wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;
or an Exendin-4 derivative of the sequence
des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),
H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,
des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,
des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;
or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.
Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.
A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium.
Antibodies are globular plasma proteins (˜150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.
The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.
There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.
Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.
In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals.
Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity.
An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H—H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv).
Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington's Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology.
Pharmaceutically acceptable solvates are for example hydrates.
It will be further apparent to those skilled in the pertinent art that various modifications and variations can be made to the present invention without departing from the spirit and scope of the invention. Further, it is to be noted, that any reference signs used in the appended claims are not to be construed as limiting the scope of the present invention.